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Methods of medical treatment and methods of medical diagnosis have long been recognized as patentable subject matter in the United States. However, recent decisions from the US Supreme Court as well as the Court of Appeals for the Federal Circuit (the court that hears appeals of patent cases) have placed restrictions on the scope of such claims.

Patent claims to diagnostic methods typically recite steps of a) sample collection, b) detection, quantification or analysis of one or more components of the sample, and c) making a diagnosis or altering a treatment based on results obtained in step b). However, court decisions over the years have limited what can be patented. In Mayo Collaborative Services v. Prometheus Laboratories, Inc.[i] the Supreme Court stated that patentable subject matter does not include certain judicial exceptions, i.e., laws of nature, natural phenomena, and abstract ideas, and that simply appending conventional steps, specified at a high level of generality, to a law of nature, a natural phenomenon or an abstract idea cannot confer patentability. To be patentable, a claim directed to a judicial exception must contain additional elements that add something “significantly more” than the law, phenomenon or abstract idea itself. In a subsequent decision, Alice Corp. v. CLS Bank Int’l, U.S.,[ii] the Supreme Court set out a two-part test for patent eligibility: first, a court (or the Patent Office) determines whether a claim is directed to a patent-ineligible concept, i.e., is the claim drawn to a law of nature, a natural phenomenon or an abstract idea. If so, the court then asks if the claim includes something “significantly more” than the patent-ineligible judicial exception.

In Mayo, the independent patent claim the Court considered was drawn to a method of optimizing therapeutic efficacy for treatment of an inflammatory bowel disease with a 6-mercaptopurine (6-MP) drug. The claim included steps of (a) administering a 6-MP drug to a patient and (b) determining the level of a 6-MP metabolite, 6-thioguanine (6-TG) in red blood cells from the patient. The claim further included how the levels of 6-TG are to be interpreted: if below a certain specified minimum, the amount of the 6-MP drug needs to be increased (presumably to be effective); if above a certain specified maximum, the dosage needs to be reduced (presumably to avoid toxicity).[iii]

In Mayo, the scientific insights included understanding that 6-mercaptopurine is metabolized to 6-thioguanine, that 6-TG levels can be used to determine proper dosage of 6-MP, and the optimal range for 6-TG levels. For a scientist, how one determines 6-TG levels is of relatively minor interest. The claim in Mayo thus included no limitation on the type of assay to determine the level of 6-TG. However, this led the Supreme Court to state that “The ‘determining’ step tells a doctor to measure patients' metabolite levels, through whatever process the doctor or the laboratory wishes to use.” (Emphasis added.) The Court added that “because methods for making such determinations were well known in the art, this step simply tell doctors to engage in well-understood, routine, conventional activity previously engaged in by scientists in the field…” The claim was deemed patent ineligible because the Court considered the conversion of 6-MP by the body to 6-TG, as well as the effective and toxic levels of 6-TG, to be non-patentable natural phenomena. Furthermore, the claim preempted all possible tests for measuring 6-TG, i.e., it covered measuring 6-TG at a high level of generality—through whatever process the doctor or the laboratory wishes to use.

The patent also issued with dependent claims specifying a particular test for measuring 6-TG: the use of high pressure liquid chromatography (HPLC).[iv] However, the Supreme Court ignored these claims, stating “For present purposes we may assume that the other claims in the patents do not differ significantly from claim 1.” The Court did not to consider that alternative methods were available for measuring 6-TG without using HPLC; it also ignored that the patent specification explicitly described such alternatives (such as thin layer chromatography), without claiming them.[v] We are thus left without any guidance as to whether a claim that included a step of “(b) determining the level of 6-TG by an HPLC assay” would have satisfied the Supreme Court. Put another way, we do not know if the Supreme Court would have considered a claim specifying an HPLC assay to measure 6-TG would amount to something “significantly more” than a claim to the phenomenon itself.

After the Supreme Court’s Mayo decision, the Court of Appeals for the Federal Circuit decidedAriosa Diagnostics, Inc. v. Sequenom, Inc.[vi] In their patent, the inventors described and claimed a polymerase chain reaction (PCR)-based method to detect cell-free fetal DNA (cffDNA) in a plasma or serum sample from a pregnant woman.[vii] There is no dispute that the presence of cffDNA in maternal plasma or serum is a natural phenomenon. There is also no dispute that the invention is useful, as providing in many cases a simpler, safer alternative to amniocentesis for analyzing fetal DNA.

The first independent claim considered by the Federal Circuit included steps of “amplifying” and “detecting” a paternally inherited nucleic acid of fetal origin. However, the claim did not specify any particular method of either “amplifying” or “detecting” paternally inherited nucleic acid from serum or plasma. Because the “amplifying” and the “detecting” steps are stated at a high level of generality, the Federal Circuit concluded that the claim was drawn to patent ineligible subject matter under the Mayo framework. In addition, claim 2 depending from claim 1 recited amplification by polymerase chain reaction, and claim 4 depending from claim 1 recited using “a sequence specific probe.” Other claims were somewhat more specific. For example, claim 5 referred to detection of Y chromosome fetal DNA. Nonetheless, claim 1 would have precluded the use of any DNA amplification technology for detecting a paternally inherited nucleic acid of fetal origin in maternal blood. Although alternatives to PCR were mentioned in the specification, such as a ligase chain reaction, nucleic acid sequence based amplification (NASBA), and branched DNA methods, the Federal Circuit concluded the claims were patent-ineligible, as they were deemed as amounting to general instructions to doctors to apply routine, conventional techniques to detect cffDNA. The Federal Circuit did not consider that a claim specifying a PCR test would not cover “whatever process the doctor or the laboratory wishes to use” in view of the availability of alternatives to PCR assays.

In addition, none of the claims recited specific sequences of oligonucleotide primers or probes for performing the PCR amplifications. We do not know if the Federal Circuit or Supreme Court would deem claims reciting specific sequences for PCR primers as adding something “significantly more” than the phenomenon itself.

The US Patent and Trademark Office recently released a guidance on subject matter eligibility, including examples of hypothetical claims to diagnostic methods and how they would be analyzed in view of Mayo and Ariosa.[viii] In their guidance, the PTO included claims to methods for diagnosing “julitis” that involve detection of “JUL-1” protein. The fact pattern included that anti-JUL-1 antibodies can occur naturally (e.g., a human anti-JUL-1 antibody from a patient with julitis), or can be generated by human effort (e.g., by inoculating pigs with JUL-1 to produce a porcine anti-JUL-1 antibody). Included in the fact pattern is that porcine anti-JUL-1 antibody had not been routinely used to detect human JUL-1.

The claims analyzed by the PTO included the following:

1. A method of detecting JUL-1 in a patient, said method comprising:

a. obtaining a plasma sample from a human patient; and

b. detecting whether JUL-1 is present in the plasma sample by contacting the plasma sample with an anti-JUL-1 antibody and detecting binding between JUL-1 and the antibody.

2. A method of diagnosing julitis in a patient, said method comprising:

a. obtaining a plasma sample from a human patient;

b. detecting whether JUL-1 is present in the plasma sample by contacting the plasma sample with an anti-JUL-1 antibody and detecting binding between JUL-1 and the antibody; and

c. diagnosing the patient with julitis when the presence of JUL-1 in the plasma sample is detected.

3. A method of diagnosing julitis in a patient, said method comprising:

a. obtaining a plasma sample from a human patient;

b. detecting whether JUL-1 is present in the plasma sample by contacting the plasma sample with a porcine anti-JUL-1 antibody and detecting binding between JUL-1 and the porcine antibody; and

c. diagnosing the patient with julitis when the presence of JUL-1 in the plasma sample is detected.

Rather bizarrely, the USPTO decided that claims 1 and 3 are patent eligible, but claim 2 is not. Claims 1 and 2 include identical steps of a. obtaining a plasma sample, and b. using an anti-JUL-1 antibody to detect JUL-1 protein. According to the PTO, claim 1 is patent eligible, in that the steps of obtaining a plasma sample from a patient and detecting whether JUL-1 is present using an anti-JUL-1 antibody do not describe any recognized judicial exception (i.e., a law of nature, a natural phenomenon or an abstract idea). The preamble of claim 1 recites a method of detecting JUL-1, and according to the PTO, claim 1 is “focused on a process of detecting whether JUL-1 is present in a plasma sample.”

On the other hand, the preamble of claim 2 recites a method of diagnosing julitis, and according to the PTO, step c of claim 2 describes a correlation or relationship between the presence of JUL-1 in a patient’s plasma and a diagnosis of julitis. Such a correlation is not patent eligible under the PTO’s interpretation of Mayo. According to the PTO, the presence of steps a and b, identical to claim 1, do not offset that claim 2 as a whole is directed to a judicial exception when step c is considered.

Does claim 2 include something “significantly more” than a judicial exception? According to the PTO, “Detecting whether JUL-1 is present in the plasma sample merely instructs a scientist to use any detection technique with any generic anti-JUL-1 antibody.” The PTO concluded that claim 2 does not present anything “significantly more” than the phenomenon itself.

In contrast, claim 3 recites diagnosing julitis using a porcine anti-JUL-1 antibody. According to the PTO, reciting the use of a porcine anti-JUL-1 antibody, rather than “any” anti-JUL-1 antibody, renders the claim patent eligible. Because porcine anti-JUL-1 antibodies were not routinely or conventionally used to detect JUL-1, the PTO considers the detection of JUL-1 using a porcine antibody to be an unconventional step that is significantly more than an application of well-understood, routine or conventional techniques.

Mayo and Ariosa do not exclude from patentability all claims to diagnostic methods. To the contrary: the Supreme Court stated in Mayo and elsewhere the well-recognized doctrine that a new combination of steps in a process may be patentable even though all the constituents of the combination were well known and in common use before the combination was made. Decisions on patent eligibility in the wake of Mayo unfortunately focus not on this doctrine, but on whether a claim involves “well-understood, routine, conventional activity.” The real question should be if a claim is directed to a (non-patentable) scientific result rather than how the result is achieved. If results are obtained by unspecified methods—through “whatever process a doctor or the laboratory wishes to use” —such claims may be patent ineligible as directed towards a natural phenomenon without adding something “significantly more.” On the other hand, claims to diagnostic methods that specify the type of test used, when there are at least conceivable alternatives, should be deemed patent eligible.

Unfortunately, the Supreme Court recently declined to review the Ariosa decision. Mayo and Ariosa will remain the law of the land until another case reaches the Court or Congress acts, and more guidance is provided that better defines something “significantly more” to make a claim patent eligible. Until the Supreme Court or Congress decides to take up patent eligibility again, we will need to live with a standard that a claim to a method that involves “well-understood, routine, conventional activity” may be patent ineligible, even when a particular test is specified and alternatives are available so that the claim is not attempting to cover a diagnostic measurement through “whatever process a doctor or the laboratory wishes to use.”

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May 12, 2017

Methods of Diagnosis under 35 U.S.C. §101: All the way with cDNA

In the wake of Alice,[1]Mayo,[2]Myriad,[3] meeting the requirement for patentable subject matter under 35 U.S.C. §101 has become increasingly difficult for claims to diagnostic methods. cDNA provides one possible route to patentability.

Under the Alice framework, in order to reject a claim under 35 USC §101, the Office must show first, that a claim is drawn to a judicial exception--i.e., a law of nature, an abstract idea, or a natural phenomenon (Alice step 1)), and if so, that the claim does not recite elements that add something “significantly more” than the exception (Alice step 2).[4] With regard to process claims, the Court has asserted that to transform an unpatentable law of nature into a patent-eligible application of such a law, one must do more than simply state the law of nature while adding the words “apply it.”[5]

However, the Supreme Court has held that cDNA is not a product of nature, and is patent eligible under 35 USC §101.[6] Indeed, the Supreme Court has stated that “the lab technician unquestionably creates something new when cDNA is made.”[7] For claims that involve detection of a pathogen or a genetic mutation, one possible avenue is detection of cDNA.

Hypothetical claims could be:

1. A method of detecting julivirus 1 in a subject, comprising: a) providing cDNA from RNA comprising a biological sample obtained from a subject; b) providing cDNA from RNA comprising a control sample; c) detecting in each sample the quantity of julivirus 1 cDNA by a PCR assay using a pair of primers that hybridize under stringent conditions to julivirus 1; and d) determining the magnitude of difference between the quantity of julivirus 1 in saidbiological sample relative to the quantity of julivirus 1 in said control sample, wherein a statistically significant increase in the quantity of julivirus 1 in said subject relative tothe control, indicates julitis and/or julitis progression in said subject.

2. A method of detection julivirus 1 in accordance with claim 1, wherein each primer has at least 70% sequence identity to a sequence selected from the group consisting of ACGTACGTACGTACGTATGC (SEQ ID NO: 1) and TGGAAGGDTGTCAACCAAATT (SEQ ID NO:2).

The Office may reject such claims under 35 USC §101 and allege that the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea), without significantly more. The Office may assert that the steps of obtaining a sample, synthesizing cDNA from RNA in sample, and detecting the presence of a sequence having at least 70% identity to SEQ ID NO: 1 by PCR are well-understood, routine and conventional activity for those in the field of diagnostics.

However, the Office would need to show that synthesizing cDNA amounts to a judicial exception under 35 USC §101. But as discussed above, the Supreme Court has held precisely the opposite, i.e., that cDNA is not a product of nature, and is patent eligible under 35 USC §101. Thus the PTO would be failing to get past Step 1 of Alice, and there would be no need to address Step 2.

In this connection, the Office must consider that the Supreme Court has repeatedly asserted that a new combination of steps in a process claim may be patentable even though all the constituents of the combination were well known and in common use before the combination was made.[8] Furthermore, a recent guidance from the PTO regarding eligibility under 35 USC §101 instructs examiners to “identify any additional elements (specifically point to claim features/limitations/steps) recited in the claim beyond the identified judicial exception.”[9]

The burden is thus on the PTO to show that the recitation of “synthesizing cDNA” in a claim does not go beyond a judicially identified exception, i.e., the PTO must show that synthesizing cDNA is merely stating a law of nature, a natural phenomenon, or an abstract idea, and adding “apply it”, when the Supreme Court has stated otherwise.